Proton pump inhibitors (PPI) play an important role in the stabilization of clot formation, especially in bleeding peptic ulcers, through pH-dependent factors by raising the pH to 6 and improving platelet aggregation [34]. Raising the pH may also decrease pepsin-mediated clot lysis and fibrinolytic activity.

A Cochrane systematic review and meta-analysis of six randomized controlled trials (2223 patients) comparing PPI with either placebo or histamine-2 (H2) receptor antagonists found no evidence that pre-endoscopic administration of PPI led to a reduction in rebleeding, mortality, or need for surgery [35]. However, the use of pre-endoscopic PPI may obviate the need for endoscopic intervention by downstaging high-risk endoscopic stigmata (Forrest classification) into low-risk lesions (Table 3.3). Given its safety profile and beneficial effect on the need for endoscopic therapy, the use of PPI in the setting of acute NVUGIB is useful, especially in patients with high-risk stigmata. Moreover, the administration of PPI may prove advantageous when early endoscopy is not feasible or local expertise is limited. Pre-endoscopic PPI, however, should not be used to delay or replace endoscopy [39]. Intravenous administration may be preferred to oral dosing on the basis of evidence supporting the former; it may also be more conducive for patients who are at risk for emesis. An initial bolus of 80 mg of omeprazole or pantoprazole, followed by an infusion of 8 mg/h, is recommended, although a lower dosage may also be effective [9, 40].

In the absence of an impact on major clinical endpoints, cost may be a more relevant variable. Cost-effectiveness analysis in US and Canadian settings reveals that pre-endoscopic PPIs are slightly more costly but effective than no administration [41]. Such conclusions may vary depending on the elapsed time to endoscopy (early versus delayed), the underlying stigmata of recent bleeding (favoring HRS), and the proportion of patients with variceal bleeding [39].

The role of the nasogastric tube (NGT) in the initial assessment of patients presenting with suspected UGIB remains controversial. Its insertion is recommended in selected patients [32], at least for sampling purposes, as it carries prognostic value in identifying endoscopic HRS [42]. However, NGT aspirates can be negative in up to 15 % of cases with UGIB, especially when bleeding stems from a duodenal source [42]. The presence of fresh blood in the NGT aspirate is an independent predictor of adverse outcome on multivariate analysis [43] and a predictor of high-risk lesions in patients who are hemodynamically stable without hematemesis. In the Canadian RUGBE study, a bloody NGT aspirate exhibited a specificity of 75.8 % for endoscopic HRS, whereas a clear NGT aspirate had a predictive value of 85.3 % for low-risk endoscopic lesions [42].

Therefore, pre-endoscopic use of NGT in selected, stable patients without hematemesis may be beneficial in predicting high-risk lesions at endoscopy and may aid the clinician in selecting patients for prompt endoscopy and pre-endoscopic administration of high-dose PPI. However, caution must be taken when using the NGT as a prognostic tool since high-risk lesions located in the duodenum may yield a clear nasogastric aspirate.

The use of nasogastric lavage is no longer indicated, especially with evidence supporting the use of prokinetics in this setting. Meta-analyses show that erythromycin is associated with a decrease need for repeat endoscopy in patients with evidence of ongoing bleeding or suspected retained blood in the stomach (hematemesis, coffee ground vomitus, or bloody NGT aspirate) [44]. However, it failed to change outcomes in terms of length of stay (LOS), transfusion requirements, and need for surgery [45]. The data stem from a limited number of studies and patients, and, thus, the robustness of these conclusions needs validation in larger trials. Current guidelines do not recommend the routine administration of prokinetic agents but support their use in selected patients with evidence of active bleeding and/or suspected blood in the stomach [2]. In terms of dosing, erythromycin should be administered intravenously 20–120 min prior to endoscopy at a dose of 250 mg over 5–30 min [45]. Since erythromycin is known to prolong the QT interval, an electrocardiogram prior to its use is advisable. Metoclopramide may be used as an alternative prokinetic agent, although data on the administration of erythromycin are more robust [45].

Practice guidelines recommend early endoscopy (defined as within 24 h of presentation) in most patients with NVUGIB [2]. In randomized trials, very early endoscopy (<12 h) did not appear to confer any additional benefits in terms of rebleeding, need for surgery, or mortality in unselected patients with NVUGIB when compared to early endoscopy (>12 h to <24 h) [46–48]. However, a recent observational study suggested that endoscopy within 13 h of presentation was associated with lower mortality in selected high-risk patients, defined as GBS >12 [49]. In accordance with previous studies, there was no benefit in mortality rate when endoscopy was performed within 13 h in low-risk subjects. Despite confounding bias, these data highlight the importance of proper risk stratification and its potential impact on the selection of individuals for very early endoscopy. Moreover, another observational study recently demonstrated that endoscopy performed within 12 h was associated with increased efficiency of care and improved control of hemorrhage in high-risk patients [50], supporting a recent UK guideline that recommends endoscopy immediately following resuscitation in patients at increased risk of negative outcomes [51].

In accordance with current international consensus guidelines, we advocate early endoscopy (within 24 h of presentation) in most patients with NVUGIB [2]. Although the evidence does not support very early endoscopy (within 12 h of presentation) on a routine basis, high-risk patients, as predicted by prognostic scales, may be considered for more urgent endoscopy, although such an approach needs validation from larger trials. Of note, however, guidelines do recommend endoscopy within 12 h of presentation in patients with suspected variceal bleeding, based on limited high-quality data [52].

Endoscopic therapy is indicated in patients presenting with NVUGIB and HRS, as defined by the Forrest classification : active spurting (Ia), active oozing (Ib), non-bleeding visible vessel (IIa), and adherent clot (IIb) (Table 3.3) [37]. Meta-analyses have demonstrated that endoscopic therapy (injection or thermal) of ulcers with these features significantly improved the rates of rebleeding, surgery, and/or mortality [53, 54]. Low-risk lesions, such as ulcers with flat, pigmented spots (Forrest IIc) and clean-based ulcers (Forrest III), are associated with lower incidences of rebleeding, and endoscopic therapy has not been shown to be beneficial in this setting [37, 55].

In terms of endoscopic hemostasis, clip placement, thermocoagulation, and sclerosant injection are effective modalities in treating ulcers with HRS [2]. These modalities, when used as monotherapy or in combination with epinephrine injection, are superior to epinephrine injection alone in terms of initial hemostasis and rebleeding rates (mono vs. epinephrine OR (odds ratio) 0.3 [0.22–0.41]; combo vs. epinephrine OR 0.53 [0.40–0.69]), need for surgery (mono vs. epinephrine OR 0.44 [0.20–0.98]; combo vs. epinephrine OR 0.64 [0.46–0.90]), and, in some studies, mortality (mono vs. epinephrine OR 0.37 [0.10–1.37]; combo vs. epinephrine OR 0.51 [031–0.84]) [56, 57]. Thus, epinephrine injection alone is not recommended as definitive treatment. When combination therapy was compared to monotherapy with clips, thermocoagulation, or sclerosant injection, both were shown to be equally efficacious [56–60]. At present, there are insufficient data to recommend one modality over the other; however, contact thermal devices, clips, and combination therapy may have the strongest evidence for use [2]. The following summarizes the five meta-analyses that assessed the efficacy of different endoscopic modalities in NVUGIB.

The meta-analysis by Calvet et al. encompassed 16 studies and compared the use of epinephrine injection alone to epinephrine injection followed by a second endoscopic therapy (1673 patients) [56]. The hemostatic modalities included injection therapies (epinephrine, thrombin, ethanolamine, ethanol, sodium tetradecyl sulfate, polidocanol, and fibrin glue), thermal modalities (laser, heat probe, bipolar electrocoagulation), and clips. The analysis concluded that the addition of a second endoscopic modality, irrespective of the type, after epinephrine injection decreased further bleeding (OR 0.53 [040–0.69]), mortality (OR 0.51 [0.31–0.84]), and emergency surgery (OR 0.64 [0.46–0.90]) compared to epinephrine injection alone.

Marmo et al. compared combination therapy (injection plus thermal or mechanical) versus monotherapy for the treatment of high-risk bleeding peptic ulcers in an analysis that included 22 studies (2474 patients) [59]. Compared to epinephrine injection alone, combination therapy was associated with significantly lower rates of recurrent bleeding (OR 0.33 [0.17–0.63]) and need for surgery (OR 0.21 [0.07–0.60]), but not mortality (OR 0.99 [0.20–4.96]). Combination therapy was not significantly better than either thermal or mechanical monotherapy.

Sung et al. assessed 15 randomized trials (1156 patients) in a meta-analysis that compared clips vs. injection alone, clips plus injection vs. injection alone, and clips vs. thermocoagulation, with or without injection [60]. Although a high degree of heterogeneity was noted across the trials, the use of clips, with or without injection, was associated with decreased rebleeding (OR 0.47 [0.28–0.76]) and need for surgery (OR 0.23 [0.08–0.70]), but not mortality (OR 1.35 [0.25–7.14]), relative to injection therapy alone. No significant differences were noted between thermocoagulation and clips.

Barkun et al. performed a meta-analysis of 41 trials (4261 patients) using endotherapy in patients with high-risk bleeding ulcers [58]. Endoscopic therapy using any modality outperformed pharmacotherapy at reducing the rebleeding rate (OR 0.35 [0.27–0.46]), but not surgery or mortality. Injection therapy was inferior to all other endoscopic modalities, except for thermal coagulation, in which a trend favored the latter but failed to reach significance. Data were insufficient to support the combined use of injection with thermal or mechanical therapy. On the basis of the study findings and subgroup analyses, the authors concluded that thermal therapy or endoscopic clips should be used alone or in combination with epinephrine injection in NVUGIB with HRS.

The meta-analysis by Laine et al. yielded similar conclusions by analyzing randomized trials that used rebleeding as the primary outcome while excluding those that incorporated second-look endoscopy (re-treatment when needed). Endoscopic therapy, when compared to pharmacotherapy, was associated with decreased rates of rebleeding and need for surgery, except in the adherent clot subgroup where no differences were detected. Epinephrine injection alone was inferior at reducing further bleeding compared to other modalities. In accordance with other studies, endoscopic clip placement and thermal therapy were equally efficacious, with or without injection therapy (Fig. 3.1).

It is recommended that high-dose intravenous PPI therapy (e.g., a PPI at a dose of 80 mg bolus dose followed by 8 mg/h infusion) should be administered to patients with HRS who underwent successful endoscopic therapy [2]. In terms of duration, high-dose PPI should be continued for 72 h post-endoscopic therapy based on the understanding that most high-risk lesions require 3 days to evolve to a low-risk lesion and that, consequently, the majority of rebleeding will occur during this time period [75]. These recommendations are based on a meta-analysis of randomized controlled trials encompassing 5792 patients in whom PPI therapy reduced the incidence of rebleeding (OR 0.45, 95 % CI 0.36–0.57) and need for surgery (OR 0.56, 95 % CI 0.45–0.70), but not mortality (OR 0.90, 95 % CI 0.67–1.19) [75–82]. Subgroup analysis of trials from Asia and a meta-analysis by Laine and McQuaid, however, showed that the administration of high-dose intravenous PPI following successful endoscopic therapy improved mortality [57]. Low-dose PPI has been shown to exhibit similar effectiveness to high-dose PPI, although this approach is not favored in consensus statements due to significant methodological limitations in reported studies [2, 83]. In terms of cost-effectiveness, the use of high-dose PPI following successful endoscopic therapy is more effective and less costly than no PPI [84–86]: the cost of PPI therapy is relatively lower than the incremental expenses attributable to one additional rebleeding episode. All patients should be on a single oral dose of a PPI daily at the time of discharge. The duration of PPI is determined by the underlying etiology of the bleeding etiology, with consideration for double-dose oral PPI if bleeding was the result of esophagitis [2].

Rebleeding after initial hemostasis occurs in 10–20 % of patients [36, 87, 88] and is in and of itself a predictor of mortality [89]. Predictors of rebleeding include comorbid illnesses, hemodynamic instability, active bleeding at endoscopy, large ulcer size (>2 cm), ulcer location (posterior duodenal wall and lesser gastric curvature), hemoglobin <10 g/dL, and transfusion requirements [88, 89].

A pre-planned second-look endoscopy at 16 to 48 hours should not be routinely performed. Earlier meta-analyses show that second-look endoscopy decreases rebleeding [90–92] and surgery [92]. The applicability of these findings are limited in contemporary practice. Indeed, the studies included sub-optimal endoscopic hemostatic methods, and did not employ, for the most part, post-endoscopic IV PPI [93]. Furthermore, the benefits of a second-look endoscopy were less apparent when very-high risk patients were excluded, and when considering the economic burden it creates [92, 94]. Although we do not routinely recommend second-look endoscopy, it may be considered in patients at an especially high risk for rebleeding [2, 24].

Endoscopy should be repeated in the setting of rebleeding [2, 24]. A second attempt at endoscopic hemostasis can be successful in 73 % of patients and, when compared to surgery, is associated with lower complications without increased mortality [95]. Surgery and interventional radiology consultations should be considered with a second episode of rebleeding and are used increasingly as salvage therapies for cases that fail endotherapy. Surgical intervention and transarterial angiographic embolization (TAE) may be required in 2.3 % and 13 % of patients, respectively [96]. In this non-randomized study, mortality was noted to be higher with surgery than TAE (29 % vs. 10 %), suggesting that TAE may be the safer rescue therapy for rebleeding (Fig. 3.3) [96]. Other retrospective studies support TAE after failed endoscopic treatment, which appears comparable to surgery with regard to complications, without adversely affecting mortality [97–99].

In summary, a repeat attempt at endoscopic hemostasis is favored in the setting of rebleeding. Surgical and angiographic interventions are considered rescue therapies when endoscopic hemostasis fails or is infeasible, with emphasis on the radiological approach given its association with lower mortality relative to surgery [2].

All patients with bleeding peptic ulcers should be tested for H. pylori and receive eradication therapy, if positive [2]. A meta-analysis demonstrated that eradication of H. pylori was significantly more effective than PPI therapy alone in preventing rebleeding from peptic ulcer disease [100]. If H. pylori is not detected in the acute setting, repeat testing is indicated on the basis of a systematic review of 23 studies showing that diagnostic tests for H. pylori infection (including serology, histology, urea breath test, rapid urease test, stool antigen, and culture) demonstrate high positive predictive value (0.85–0.99) but low negative predictive value (0.45–0.75) in the setting of acute GI bleeding, with 25–55 % of H. pylori-infected patients yielding false-negative results (Fig. 3.4) [101]. The biological explanation for this high false-negative rate in the setting of acute bleeding remains unclear [102].

In patients with previous ulcer bleeding, alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) should be considered, but if required, a combination of COX-2 inhibitor along with a PPI is recommended [103, 104]. Data suggest that adding a PPI to a traditional NSAID or using a COX-2 inhibitor alone reduces the risk for upper gastrointestinal complications. However, the reduction in complications was greater with the combination of a COX-2 inhibitor and a PPI [102]. Evidence from randomized controlled trials demonstrates that COX-2 inhibitor plus PPI, when compared to COX-2 inhibitor alone, further decreases the risk of rebleeding following an episode of acute peptic ulcer hemorrhage [105–107]. On the other hand, COX-2 inhibitors may increase the risk for cardiovascular events, as shown by two meta-analyses [108, 109]. With regard to reinstituting NSAID therapy following NVUGIB, the clinician must weigh the cardiovascular risk relative to that of GI complications on a case-by-case basis. In sum, we recommend the use of a COX-2 inhibitor along with a PPI if an alternative replacement to NSAID therapy is not feasible.

In the context of acute NVUGIB, ASA can be withheld although prolonged discontinuation should be avoided. In one meta-analysis, nonadherence or withdrawal of ASA was associated with a threefold increase in major cardiac events [110]. Recently, a retrospective cohort study from Sweden showed that prolonged discontinuation of ASA for secondary cardiovascular prophylaxis following acute GI bleeding resulted in a sevenfold increase in cardiovascular events or death [111]. The time to thrombosis is usually between 7 and 30 days, which is consistent with the inhibited platelet circulation time of about 10 days [112, 113]. Controlled data suggest that cardiovascular benefits attributable to early reintroduction of ASA outweigh the risks of GI adverse events [114]. Based on these findings, consensus guidelines recommend that, in patients who receive low-dose ASA and develop acute ulcer bleeding, ASA therapy should be withheld and restarted as soon as the risk for cardiovascular complication is thought to outweigh the risk for bleeding [2].

We recommend that ASA be reintroduced within 3–5 days of the index bleed after consultation with the interested disciplines, including general practitioners, internists, cardiologists, neurologists, gastroenterologists, and intensivists. Data on the optimal management of clopidogrel and dual antiplatelet therapy in the context of acute bleeding are lacking, whereas the management of patients on oral anticoagulant is discussed below.

Peptic ulcer bleeding is a common complication of long-term ASA administration for cardiothrombotic prophylaxis [115, 116]. Both H2-receptor antagonist (H2RA) and PPI have been explored as possible gastroprotective agents in this setting. A randomized trial showed that famotidine 20 mg twice daily reduces the incidence of peptic ulcer and erosive esophagitis compared to placebo in patients on ASA at low risk of developing GI complications [117]. Furthermore, this was an endoscopic study with the primary endpoint being the presence of peptic ulcer or erosions on repeat EGD at 12 weeks. Clinical outcomes were not assessed. In another randomized trial comparing famotidine 40 mg twice a day with pantoprazole 20 mg daily, the latter was superior to H2RA in terms of reducing not only dyspepsia but also upper GI bleeding events in patients on long-term ASA and with a history of peptic ulcer disease (PUD), with or without bleeding [118]. We concur with current consensus guidelines recommending PPI prophylaxis in patients on ASA and high-risk features for GI complications, such as a previous history of PUD and/or ulcer bleeding [2].

In addition to PPI prophylaxis, patients who require long-term ASA following acute NVUGIB should undergo testing and eradication of H. pylori [2]. Controlled data show that eradication of H. pylori following ulcer bleeding is as effective as the administration of PPI in preventing recurrent bleeding while on ASA [119]. In addition, H. pylori eradication leads to very low rebleeding rates even after a period of 10 years [120]. In contrast, one study demonstrated a high rebleeding rate on ASA despite an attempt at H. pylori eradication [121], though many patients in this study failed eradication therapy. Therefore, given the variable success in treating H. pylori, we recommend H. pylori testing/eradication and the use of long-term PPI in patients requiring prolonged ASA use following an ulcer bleed [2].

Clopidogrel administration following peptic ulcer bleeding is also associated with high rebleeding rates (9–14 %) [122, 123], and coadministration of a PPI should be considered. A randomized trial comparing PPI with placebo in patients on clopidogrel with a history of PUD showed a decreased incidence of recurrent ulcer disease on endoscopy at 6 months follow-up [124]. In addition, data on the gastroprotective effect of PPI in the setting of dual antiplatelet therapy (DAPT) is well documented by the COGENT trial [125], showing a significant reduction in GI bleeding (HR 0.34 (0.18–0.63)). Thus, PPI gastroprotection is indicated in patients on clopidogrel alone when there is a history of PUD, while patients on DAPT should receive PPI routinely regardless of previous PUD status [115, 116, 126].

Of note is the potential for PPI to decrease the antiplatelet effect of clopidogrel, as suggested by pharmacokinetic studies [127–129]. Several observational studies have also demonstrated this interaction although they are confounded by covariate imbalance and statistical bias. Indeed, the attenuating effect of PPI on clopidogrel seems to be limited following multivariate adjustment [130, 131]. In addition, the COGENT trial comparing DAPT (ASA and clopidogrel) and PPI versus DAPT and placebo showed no significant difference in major cardiovascular events, although the study was terminated prematurely with a median follow-up time of 133 days [125]. Lastly, three systematic reviews assessing best quality observational studies did not show any significant interaction between PPI and clopidogrel with regard to major cardiovascular complications [131–133].